U.S. patent application number 13/931384 was filed with the patent office on 2013-11-14 for maintenance of platelet inhibition during antiplatelet therapy.
The applicant listed for this patent is The Medicines Company. Invention is credited to Clive Arthur Arculus-Meanwell, Dawn Bell, Diane Mould, Jayne Prats, Lisa Ruderman Chen, Simona Skerjanec, Meredith Todd.
Application Number | 20130303478 13/931384 |
Document ID | / |
Family ID | 49549075 |
Filed Date | 2013-11-14 |
United States Patent
Application |
20130303478 |
Kind Code |
A1 |
Ruderman Chen; Lisa ; et
al. |
November 14, 2013 |
Maintenance of Platelet Inhibition During Antiplatelet Therapy
Abstract
A method for reducing or maintaining platelet inhibition in a
patient by administering cangrelor prior to an invasive procedure
is described. The method of this invention can be used for patients
in need of antiplatelet therapy or at risk of thrombosis. The
method can further be used in patients who were previously treated
with long-acting platelet inhibitors without increasing the risk of
excessive bleeding.
Inventors: |
Ruderman Chen; Lisa; (Rye,
NY) ; Skerjanec; Simona; (Basel, CH) ; Bell;
Dawn; (Morristown, NJ) ; Prats; Jayne;
(Carlisle, MA) ; Todd; Meredith; (Hoboken, NJ)
; Arculus-Meanwell; Clive Arthur; (Bernardsville, NJ)
; Mould; Diane; (Fort Meyers, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Medicines Company |
Parsippany |
NJ |
US |
|
|
Family ID: |
49549075 |
Appl. No.: |
13/931384 |
Filed: |
June 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13209271 |
Aug 12, 2011 |
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13931384 |
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12990332 |
Aug 15, 2011 |
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PCT/US09/43820 |
May 13, 2009 |
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13209271 |
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13904778 |
May 29, 2013 |
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12990332 |
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13792056 |
Mar 9, 2013 |
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13904778 |
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12943717 |
Nov 10, 2010 |
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13792056 |
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61127414 |
May 13, 2008 |
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61260361 |
Nov 11, 2009 |
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61815735 |
Apr 25, 2013 |
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Current U.S.
Class: |
514/48 |
Current CPC
Class: |
A61K 31/7076
20130101 |
Class at
Publication: |
514/48 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076 |
Claims
1. A method of transitioning a patient from administration of
cangrelor during percutaneous coronary intervention (PCI) to
administration of cangrelor in preparation for surgery, the method
comprising: (1) administering a PCI dosing regimen, wherein the PCI
dosing regimen comprises (i) administering intravenously a 30
.mu.g/kg bolus of cangrelor before the start of PCI; and (ii)
administering intravenously a continuous infusion of cangrelor at
an infusion rate of 4 .mu.g/kg/min after administration of the
bolus; (2) discontinuing the administration of the PCI dosing
regimen; and (3) administering a bridge dosing regimen, wherein the
bridge dosing regimen comprises administering intravenously a
continuous infusion of cangrelor at an infusion rate of 0.75
.mu.g/kg/min.
2. The method of claim 1, wherein the bolus is administered in less
than one minute.
3. The method of claim 1, wherein the administration of the
continuous infusion at the infusion rate of 4 .mu.g/kg/min is
started immediately after the administration of the bolus.
4. The method of claim 1, wherein the cangrelor administered as the
bolus is in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
5. The method of claim 1, wherein the cangrelor administered as the
continuous infusion at the infusion rate of 4 .mu.g/kg/min is in a
pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
6. The method of claim, 1, wherein the cangrelor administered as
the continuous infusion at the infusion rate of 0.75 .mu.g/kg/min
is in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
7. The method of claim 1, wherein bridge dosing regimen is
administered as quickly as possible following the discontinuation
of the administration of the PCI dosing regimen.
8. The method of claim 1, wherein the discontinuation of the PCI
dosing regimen and the administration of the bridge dosing regimen
is achieved simultaneously by lowering the 4 .mu.g/kg/min infusion
rate to the 0.75 .mu.g/kg/min infusion rate.
9. The method of claim 1, wherein the administration of the bridge
dosing regimen is discontinued at least about one hour prior to
administration of anesthesia for the surgery.
10. The method of claim 1, wherein administration of the bridge
dosing regimen is discontinued after no longer than about 7 days
from initiation of the bridge dosing regimen.
11. A method of transitioning a patient from administration of
cangrelor in preparation for surgery to administration of cangrelor
during percutaneous coronary intervention (PCI), the method
comprising: (1) administering a bridge dosing regimen, wherein the
bridge dosing regimen comprises administering intravenously a
continuous infusion of cangrelor at an infusion rate of 0.75
.mu.g/kg/min; (2) discontinuing the administration of the bridge
dosing regimen; and (3) administering a PCI dosing regimen, wherein
the PCI dosing regimen comprises (i) administering intravenously a
30 .mu.g/kg bolus of cangrelor before the start of PCI; and (ii)
administering intravenously a continuous infusion of cangrelor at
an infusion rate of 4 .mu.g/kg/min.
12. The method of claim 11, wherein the patient was administered a
long-acting P2Y.sub.12 inhibitor that was discontinued prior to the
administration of the bridge dosing regimen.
13. The method of claim 11, wherein the bolus is administered in
less than one minute.
14. The method of claim 11, wherein the administration of the
continuous infusion of cangrelor at the infusion rate of 4
.mu.g/kg/min is started immediately after the administration of the
bolus.
15. The method of claim 11, wherein the discontinuation of the
bridge dosing regimen and the administration of the PCI dosing
regimen is achieved simultaneously by administering the bolus and
increasing the 0.75 .mu.g/kg/min infusion rate to the 4
.mu.g/kg/min infusion rate.
16. The method of claim 11, wherein the cangrelor administered as
the continuous infusion at the infusion rate of 0.75 .mu.g/kg/min
is in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
17. The method of claim 11, wherein the cangrelor administered as
the bolus is in a pharmaceutical composition comprising 200
.mu.g/mL of cangrelor.
18. The method of claim 11, wherein the cangrelor administered as
the continuous infusion at the infusion rate of 4 .mu.g/kg/min is
in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
19. A method of transitioning a patient from administration of
cangrelor in preparation for surgery to administration of cangrelor
during percutaneous coronary intervention (PCI), the method
comprising: (1) administering a bridge dosing regimen, wherein the
bridge dosing regimen comprises administering intravenously a
continuous infusion of cangrelor at an infusion rate of 0.75
.mu.g/kg/min; (2) discontinuing the administration of the bridge
dosing regimen; and (3) administering a PCI dosing regimen, wherein
the PCI dosing regimen comprises administering intravenously a
continuous infusion of cangrelor at an infusion rate of 4
.mu.g/kg/min during PCI.
20. The method of claim 19, wherein the patient was administered a
long-acting P2Y.sub.12 inhibitor that was discontinued prior to the
administration of the bridge dosing regimen.
21. The method of claim 19, wherein the discontinuation of the
bridge dosing regimen and the administration of the PCI dosing
regimen is achieved simultaneously by increasing the 0.75
.mu.g/kg/min infusion rate to the 4 .mu.g/kg/min infusion rate.
22. The method of claim 19, wherein the cangrelor administered as
the continuous infusion at the infusion rate of 0.75 .mu.g/kg/min
is in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
23. The method of claim 19, wherein the cangrelor administered as
the continuous infusion at the infusion rate of 4 .mu.g/kg/min is
in a pharmaceutical composition comprising 200 .mu.g/mL of
cangrelor.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This invention is a continuation-in-part of U.S. application
Ser. No. 13/209,271 filed on Aug. 12, 2011, which is a
continuation-in-part of U.S. application Ser. No. 12/990,332 filed
on Aug. 15, 2011, which is a National Stage Entry of
PCT/US09/043,820 filed on May 13, 2009, which claims priority to
U.S. provisional application Ser. No. 61/127,424 filed on May 13,
2008. This invention is also a continuation-in-part of U.S.
application Ser. No. 13/904,778 filed on May 29, 2013, which is a
continuation-in-part of U.S. application Ser. No. 13/792,056 filed
on Mar. 9, 2013, which is a continuation-in-part of U.S.
application Ser. No. 12/943,717 filed on Nov. 10, 2010, which
claims priority to U.S. provisional application Ser. No. 61/260,361
filed on Nov. 11, 2009. U.S. application Ser. No. 13/904,778 also
claims priority to U.S. provisional application Ser. No. 61/815,735
filed on Apr. 25, 2013. Each of the above-referenced applications
is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The instant invention relates to the field of platelet
inhibition, and in particular to methods of maintaining or reducing
platelet activity in patients undergoing an invasive procedure.
BACKGROUND OF THE INVENTION
[0003] Antiplatelet therapy has been shown to reduce clinical
ischemic events and improve outcomes for acute coronary syndrome
(ACS) patients. Currently, the approved antiplatelet products
include aspirin and thienopyridines, such as clopidogrel and
ticlopidine. One of the most widely prescribed thienopyridines is
clopidogrel, which is also known as Plavix.RTM..
[0004] Thienopyridines such as clopidogrel irreversibly inhibit
P2Y.sub.12 receptors, which play an active role in platelet
activation. In the normal state, when blood vessels are damaged,
platelet activation mediated by P2Y.sub.12 receptors play an
important role to arrest bleeding at the site of injury. In a
diseased state, platelet activation leads to vascular occlusion and
ischemic damage. Thus, P2Y.sub.12 receptor antagonists play a key
role in antiplatelet therapy in assisting to prevent coronary
artery disease and for the immediate treatment of ACS and
percutaneous coronary intervention (PCI).
[0005] Physicians often prescribe dual antiplatelet therapy, which
include aspirin and a thienopyridine such as clopidogrel, as a
first line treatment for patients who have been diagnosed with ACS
or who are showing symptoms associated with ACS. Pending further
examinations, these patients may continue with this treatment or
receive other treatments such as coronary artery bypass grafting
(CABG) and PCI. Consistent with this practice, current American
College of Cardiology/American Heart Association (ACC/AHA)
guidelines recommend immediate initiation of dual antiplatelet
therapy of clopidogrel and aspirin after a patient is diagnosed
with ACS. Similarly, patients who have received a bare metal stent
or drug-eluting stent are also put on the dual clopidogrel and
aspirin therapy for an extended period of time to prevent an
ischemic event. For instance, a post hoc analysis of a blinded,
placebo-controlled trial suggests a benefit of platelet activity
inhibition in terms of decreased thrombotic events prior to CABG
(Fox K A et. al, Circulation. 2004; 110; 1201-08). For many
patients, this dual antiplatelet therapy provides tremendous
clinical benefits, and minimizes the risks of ischemic events, such
as heart attack and stroke.
[0006] Dual antiplatelet therapy, however, has drawbacks. Cessation
of clopidogrel may increase the incidence of ischemic events in the
short-term due to a "rebound" effect of platelet activation
(Brilakis E S et al, J Am Coll Cardiol. 2007 Jun. 5; 49(22):
2145-50; Ho P M et al, JAMA. 2008 Feb. 6; 299(5): 532-9).
[0007] In addition patients receiving dual antiplatelet therapy
experience an increased incidence of blood transfusions and
bleeding complications while undergoing surgery and other invasive
procedures. This is particularly true for ACS patients who often
receive surgery, such as CABG and PCI, and other invasive
procedures, such as implantation of a bare metal stent (BMS) or
drug-eluting stent (DES). Because aspirin and thienopyridines are
irreversible, long-acting platelet antagonists, reversal of the
inhibition of platelet function occurs only as new platelets are
generated; therefore, even after discontinuation, their effect can
last several days before being completely eliminated.
[0008] Thus, for patients under dual therapy who also require
surgery such as CABG, sustained platelet inhibition poses an
unacceptable risk of bleeding. Consequently, it has been
recommended by the ACC/AHA and the Society of Thoracic Surgeons
(STS) guidelines to cease thienopyridine therapy prior to
undergoing non-emergent cardiac surgical procedures to minimize
bleeding risks. Hence, patients are often required to stop dual
antiplatelet therapy and wait for five to seven days before any
invasive procedures can be performed.
[0009] On the other hand, even though clopidogrel treatment prior
to CABG does increase bleeding due to its irreversibility, platelet
P2Y.sub.12 inhibition appears to prevent ischemic events in
patients requiring CABG. As a result, physicians often face the
difficult choice of discontinuing clopidogrel and aspirin prior to
surgery and risking a potential ischemic event in the unprotected
perioperative period or delaying surgery until the time at which
clopidogrel is no longer required.
[0010] Currently, no ultra short-acting platelet inhibitors are
available that allow maintenance of platelet inhibition before an
invasive procedure without increasing bleeding complications at the
time of the invasive procedure. Potentially, effective platelet
inhibition with an ultra short-acting platelet inhibitor during the
period of clopidogrel withdrawal may protect patients from ischemic
events and also preserve normal hemostasis at the time of
surgery.
[0011] Therefore, a need exists for a new therapy for patients who
are undergoing surgery (this includes therapy prior to, during, and
post) or other invasive procedures, and who have a need for
antiplatelet therapy. This new therapy should maintain platelet
inhibition at acceptable levels while allowing for rapid
restoration of platelet function after discontinuation, thereby
"bridging" patients to their surgical procedures without increasing
the risk of bleeding complications.
[0012] In addition, a need exists for a new therapy for patients
who, for whatever reason, cannot be administered thienopyridines,
such as clopidogrel or Plavix.RTM., or cannot receive orally
administered antiplatelet therapies.
SUMMARY OF THE INVENTION
[0013] As shown herein, the present invention describes
compositions and methods of maintaining or reducing platelet
activity in a patient prior to the patient undergoing an invasive
procedure by administering an effective amount of short-acting
P2Y.sub.12 inhibitor.
[0014] In one aspect of this invention methods are described for
administering an effective amount of a short-acting P2Y.sub.12
inhibitor to maintain or reduce platelet activity in a patient
before an invasive procedure, in a patient previously treated with
long-acting irreversible platelet inhibitors without an increase
risk in bleeding.
[0015] In a related embodiment of this method, other therapeutic
agents are administered concurrently with the reversible,
short-acting P2Y.sub.12 inhibitor.
[0016] In another related embodiment of this method, the risk of
bleeding is not increased.
[0017] In another aspect of this invention, a short-acting
P2Y.sub.12 inhibitor is used to maintain or reduce platelet
activity in a patient perioperatively where oral antiplatelet
therapy is contraindicated. The reversible, short-acting P2Y.sub.12
inhibitor can be administered to a patient as a bolus and or a
continuous intravenous infusion.
[0018] In another aspect of this invention, methods are described
where an effective amount of a short-acting P2Y.sub.12 inhibitor is
administered to sufficiently reduce or maintain at least 60%
platelet inhibition or PRU values less than 240 prior to the
patient undergoing an invasive procedure.
[0019] In a related embodiment to this method, the short-acting
P2Y.sub.12 inhibitor is discontinued thereby allowing platelet
activity to return to pre-administration levels as measured by PRU
being greater than 240.
[0020] In yet another aspect of the present invention, methods are
described for administering a reversible, short-acting P2Y.sub.12
inhibitor to a patient who was previously administered a
thienopyridine, and ceasing administration of the short-acting
P2Y.sub.12 inhibitor wherein the PRU levels is similar to
pre-administration levels of the short-acting P2Y.sub.12 inhibitor,
prior to said patient undergoing an invasive procedure.
[0021] In another aspect of this invention, a method of treating or
preventing thrombosis is described by administering a short-acting
P2Y.sub.12 inhibitor to a patient previously treated with a
long-acting irreversible platelet inhibitor, where the risk of
bleeding is not increased.
[0022] In another aspect of this invention, an intravenous
pharmaceutical composition of cangrelor is described for
maintaining or reducing platelet inhibition.
[0023] In another aspect of this invention, a method for preparing
an intravenous cangrelor composition for inhibiting platelet
activity by combining cangrelor with mannitol, sorbitol and
intravenously administrable excipient for maintaining PRU values at
a certain level.
[0024] Aspects of the present invention relate to a method of
transitioning a patient from administration of cangrelor during PCI
to administration of cangrelor in preparation for surgery, or a
method of maintaining reduced platelet activity in a patient who is
transitioning from administration of cangrelor during PCI to
administration of cangrelor in preparation for surgery, or a method
of maintaining P2Y.sub.12 inhibition in a patient who is
transitioning from administration of cangrelor during PCI to
administration of cangrelor in preparation for surgery. These
methods may comprise (1) administering a PCI dosing regimen,
wherein the PCI dosing regimen comprises administering
intravenously a 30 .mu.g/kg bolus of cangrelor before the start of
PCI, and administering intravenously a continuous infusion of
cangrelor at an infusion rate of 4 .mu.g/kg/min after
administration of the bolus; (2) discontinuing the administration
of the PCI dosing regimen; and (3) administering a bridge dosing
regimen, wherein the bridge dosing regimen comprises administering
intravenously a continuous infusion of cangrelor at an infusion
rate of 0.75 .mu.g/kg/min.
[0025] Aspects of the present invention further relate to a method
of transitioning a patient from administration of cangrelor in
preparation for surgery to administration of cangrelor during PCI,
or a method of maintaining reduced platelet activity in a patient
who is transitioning from administration of cangrelor in
preparation for surgery to administration of cangrelor during PCI,
or a method of maintaining P2Y.sub.12 inhibition in a patient who
is transitioning from administration of cangrelor in preparation
for surgery to administration of cangrelor during PCI. These
methods may comprise (1) administering a bridge dosing regimen,
wherein the bridge dosing regimen comprises administering
intravenously a continuous infusion of cangrelor at an infusion
rate of 0.75 .mu.g/kg/min; (2) discontinuing the administration of
the bridge dosing regimen; and (3) administering a PCI dosing
regimen, wherein the PCI dosing regimen comprises administering
intravenously a 30 .mu.g/kg bolus of cangrelor before the start of
PCI, and administering intravenously a continuous infusion of
cangrelor at an infusion rate of 4 .mu.g/kg/min. In another
embodiment, the method may comprise (1) administering a bridge
dosing regimen, wherein the bridge dosing regimen comprises
administering intravenously a continuous infusion of cangrelor at
an infusion rate of 0.75 .mu.g/kg/min; (2) discontinuing the
administration of the bridge dosing regimen; and (3) administering
a PCI dosing regimen, wherein the PCI dosing regimen comprises
administering intravenously a continuous infusion of cangrelor at
an infusion rate of 4 .mu.g/kg/min.
BRIEF DESCRIPTION OF THE FIGURES
[0026] Understanding of the present invention will be facilitated
by consideration of the following detailed description of the
embodiments of the present invention taken in conjunction with the
accompanying drawings, in which like numerals refer to like parts
and in which:
[0027] FIG. 1 is a graphical presentation of the percent inhibition
of ADP-induced platelet aggregation and effect on bleeding
time;
[0028] FIG. 2 is a flow chart of the time periods through which the
present invention is performed;
[0029] FIG. 3 is a flow chart of a study demonstrating an exemplary
method;
[0030] FIGS. 4-1 and 4-2 show a table of the studied assessments by
time point;
[0031] FIG. 5 shows a comparison of PRU responses versus cangrelor
concentration for patients receiving a PCI dosing regimen and for
patients receiving a bridge dosing regimen;
[0032] FIG. 6 shows a simulated range of PRU responses for a male
patient, 62 years old and weighing 90 kg, with IV bolus loading
dose for PCI, transitioning from the bridge dosing regimen to the
PCI dosing regimen (the shaded areas are the confidence intervals
about the lines and the dashed line is the cut-off PRU value of
208, associated high sensitivity and specificity for the presence
of P2Y.sub.12 inhibition);
[0033] FIG. 7 shows a simulated range of PRU responses for a male
patient, 62 years old and weighing 90 kg, with no IV bolus loading
dose for PCI, transitioning from the bridge dosing regimen to the
PCI dosing regimen (the shaded areas are the confidence intervals
about the lines and the dashed line is the cut-off PRU value of
208, associated high sensitivity and specificity for the presence
of P2Y.sub.12 inhibition);
[0034] FIG. 8 shows a simulated range of PRU responses for a female
patient, 66 years old and weighing 60 kg, with IV bolus loading
dose for PCI, transitioning from the bridge dosing regimen to the
PCI dosing regimen (the shaded areas are the confidence intervals
about the lines and the dashed line is the cut-off PRU value of
208, associated high sensitivity and specificity for the presence
of P2Y.sub.12 inhibition);
[0035] FIG. 9 shows a simulated range of PRU responses for a female
patient, 66 years old and weighing 60 kg, with no IV bolus loading
dose for PCI, transitioning from the bridge dosing regimen to the
PCI dosing regimen (the shaded areas are the confidence intervals
about the lines and the dashed line is the cut-off PRU value of
208, associated high sensitivity and specificity for the presence
of P2Y.sub.12 inhibition);
[0036] FIG. 10 shows a simulated range of PRU responses for male
patient, 62 years old and weighing 90 kg, transitioning from the
PCI dosing regimen to the bridge dosing regimen (the shaded areas
are the confidence intervals about the lines and the dashed line is
the cut-off PRU value of 208, associated high sensitivity and
specificity for the presence of P2Y.sub.12 inhibition);
[0037] FIG. 11 shows a simulated range of PRU responses for female
patient, 66 years old and weighing 60 kg, transitioning from the
PCI dosing regimen to the bridge dosing regimen (the shaded areas
are the confidence intervals about the lines and the dashed line is
the cut-off PRU value of 208, associated high sensitivity and
specificity for the presence of P2Y.sub.12 inhibition).
DETAILED DESCRIPTION OF THE INVENTION
[0038] It is to be understood that the figures and descriptions of
the present invention have been simplified to illustrate elements
that are relevant for a clear understanding of the present
invention, while eliminating, for the purpose of clarity, many
other elements found in typical antiplatelet therapies. Those of
ordinary skill in the art will recognize that other elements and/or
steps are desirable and/or required in implementing the present
invention. However, because such elements and steps are well known
in the art, and because they do not facilitate a better
understanding of the present invention, a discussion of such
elements and steps is not provided herein. The disclosure herein is
directed to all such variations and modifications to such elements
and methods known to those skilled in the art. Furthermore, the
embodiments identified and illustrated herein are for exemplary
purposes only, and are not meant to be exclusive or limited in
their description of the present invention.
[0039] The present invention provides a method for inhibiting
platelet reactivity in patients prior to undergoing an invasive
procedure.
[0040] The methods described in the present invention maintains
platelet inhibition at acceptable and targeted levels, while
allowing for rapid restoration of platelet function after
discontinuation of the drug therapy so that patients may undergo
invasive procedures without increasing the risk of bleeding
complications.
[0041] The described methods can be used for patients in need of
treatment to reduce or maintain platelet inhibition. Preferably the
described methods can be used in patients at risk of thrombotic
events. More preferably the embodiments of the present invention
are directed to patients diagnosed with symptoms of stable or
unstable angina, vascular ischemic events, atherosclerosis, acute
coronary syndrome, as well as STEMI or N-STEMI. The described
methods can also be used for patients having previously received a
stent, such as a bare metal stent or a drug-eluting stent, for the
treatment or prevention of stent thrombosis. While the present
invention is generally targeted for use with human patients, the
described methods can be used on any living animal.
[0042] The present invention further provides a method for reducing
or maintaining adequate P2Y.sub.12 inhibition with rapid
reversibility upon discontinuation of long-acting irreversible
platelet inhibitors prior to patients undergoing invasive
procedures without increasing the risk of bleeding
complications.
DEFINITIONS
[0043] Long-acting P2Y.sub.12 inhibitors refer to compounds which
inhibit P2Y.sub.12 receptor activities, having a slow on-set and
long elimination half-life. Examples of long-acting P2Y.sub.12
inhibitors are typically formulated as oral dosage forms. One
example of long-acting P2Y.sub.12 inhibitor is long-acting
irreversible P2Y.sub.12 inhibitors. Examples of long-acting
irreversible P2Y.sub.12 inhibitors include thienopyridines.
Examples of thienopyridines include, without limitation,
clopidogrel, ticloridine, and prasugrel and such other compounds
having similar properties. Clopidogrel is a pro-drug that requires
metabolism for conversion to the active metabolite.
[0044] Short-acting reversible, P2Y.sub.12 inhibitors refer to
compounds which inhibits P2Y.sub.12 receptor activities, having a
fast onset time and a relatively short metabolism rate as compared
to those of thienopyridines. Examples of a short-acting, reversible
P2Y.sub.12 inhibitor include, without limitations, cangrelor,
ticagrelor and PRT060128. It should be noted that the present
invention is not limited to these examples. Additional compounds
that have similar properties may also be used in the present
invention.
[0045] One particularly preferred example of a reversible,
short-acting P2Y.sub.12 inhibitor is cangrelor. Cangrelor is a
potent, direct, and reversible antagonist of the platelet
P2Y.sub.12 receptor. Cangrelor has a half-life of approximately
less than 10 minutes, allowing for a return to normal platelet
function in a very short period of time upon discontinuation of the
drug. By reducing the need for a compound to be metabolized for
activity, and by having a relatively short half-life, reversible,
short-acting P2Y.sub.12 inhibitors are considered "reversible,"
meaning that full platelet functionality may return rather quickly
as compared to thienopyridines.
[0046] The binding of cangrelor to the P2Y.sub.12 receptor inhibits
platelet activation as well as aggregation when mediated in whole
or in part via this receptor. Cangrelor can be derived completely
from synthetic materials, and is an analogue of adenosine
triphosphate (ATP). ATP is a natural antagonist of the P2Y.sub.12
receptor sites and is found in humans.
[0047] The chemical structure for cangrelor is depicted below as
Formula I.
##STR00001##
[0048] Cangrelor is clinically well tolerated and safe and has no
drug-drug interaction with aspirin, heparin or nitroglycerin.
Unlike orally dosed thienopyridines, cangrelor can be administered
intravenously and binds directly to P2Y.sub.12 receptor sites of
platelets. In each of the embodiments of the present invention, the
term "cangrelor" encompasses the compound of Formula I as well as
tautomeric, enantiomeric and diastereomeric forms thereof, and
racemic mixtures thereof, other chemically active forms thereof,
and pharmaceutically acceptable salts of these compounds, including
a tetrasodium salt. These alternative forms and salts, processes
for their production, and pharmaceutical compositions comprising
them, are well known in the art and set forth, for example, in U.S.
Pat. No. 5,721,219. Additional disclosure relevant to the
production and use of cangrelor may be found in U.S. Pat. Nos.
5,955,447, 6,130,208 and 6,114,313, as well as in U.S. Appln.
Publication Nos. 2006/0270607 and 2011/0112030.
[0049] Invasive procedures means any technique where entry to a
body cavity is required or where the normal function of the body is
in some way interrupted by a medical procedure and/or treatment
that invades (enters) the body, usually by cutting or puncturing
the skin and/or by inserting instruments into the body. Invasive
procedures can include coronary artery bypass grafting (CABG),
orthopedic surgeries, urological surgeries, percutaneous coronary
intervention (PCI), other general invasive procedures, such as
endarterectomy, renal dialysis, cardio-pulmonary bypass, endoscopic
procedures or any medical, surgical, or dental procedure that could
result in excessive bleeding or hemorrhage to the patient.
[0050] Perioperative means the period of a patient's invasive
procedure which can occur in hospitals, surgical centers or health
care providers' offices. Perioperative includes admission,
anesthesia, surgery, to recovery.
[0051] Thrombosis is the formation of a blood clot (thrombus)
inside a blood vessel obstructing the flow of blood through the
circulatory system. When a blood vessel is injured, the body uses
platelets and fibrin to form a blood clot to prevent blood loss.
Some examples of the types of thrombosis include venous thrombosis
which includes deep vein thrombosis, portal vein thrombosis, renal
vein thrombosis, jugular vein thrombosis, Budd-Chiari syndrome,
Paget-Schroetter disease, cerebral venous sinus thrombosis,
cerebral venous sinus thrombosis and arterial thrombosis which
includes stroke and myocardial infarction.
[0052] Dosage and Administration
[0053] As used herein, the terms "dose", "dosage", "unit dose",
"unit dosage", "effective dose", "effective amount" and related
terms refer to physically discrete units that contain a
predetermined quantity of cangrelor, calculated to produce a
desired therapeutic effect. These terms are synonymous with the
therapeutically effective amounts and amounts sufficient to achieve
the stated goals of the methods disclosed herein.
[0054] When administered as an intravenous (IV) formulation, a
pharmaceutical composition comprising cangrelor may be administered
as a bolus, as a continuous infusion, or as a bolus followed by a
continuous infusion. When administered as a bolus, a dose of about
5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
90, 95 or 100 .mu.g/kg cangrelor, or more, is administered to the
patient. In preferred embodiments, between about 20 .mu.g/kg and
about 40 .mu.g/kg cangrelor is administered, more preferably about
30 .mu.g/kg. When administered as a continuous infusion, cangrelor
may be administered at about 0.1, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30 .mu.g/kg/min, or more to the patient. In
preferred embodiments, between about 0.1 and about 5 .mu.g/kg/min
cangrelor is administered, more preferred is administration of
cangrelor in the range of about 0.5 .mu.g/kg/min to about 2
.mu.g/kg/min. Even more preferred is a dosage range of cangrelor at
about 0.5 .mu.g/kg/min to about 1 .mu.g/kg/min. The skilled artisan
will understand that different bolus and intravenous dosages from
those set forth here may be administered based on the particular
characteristic of the patient. Thus, the dosage amount can be
varied from the dosage amount presently described, however, the
dosage given must be sufficient to reduce or maintain the PRU
values below about 240 as measured by VerifyNow.RTM..
[0055] In addition, the skilled artisan will understand that the
exact amount of reversible short-acting P2Y.sub.12 inhibitor to be
administered to a patient will vary depending on the degree of
platelet activity inhibition that is sought. For example, the
amount of reversible short-acting P2Y.sub.12 inhibitor to be
administered to a patient during an invasive procedure that will
result in bleeding may be much less than the amount that would be
administered when such a procedure is not being performed.
[0056] The dosage of the reversible short-acting P2Y.sub.12
inhibitor may be administered as a continuous intravenous infusion
or it may be administered in discrete doses, such as between 1 and
48 doses, or more, per 24 hour period. The dosage of the reversible
short-acting P2Y.sub.12 inhibitor may vary over time, with a lower
dosage being initially administered, followed by an increased
dosage for a sustained period of time, with an optional decrease in
the dosage prior to complete cessation of administration of the
reversible short-acting P2Y.sub.12 inhibitor. Such a dosing regime
may be used in conjunction with the concurrent cessation of
thienopyridine and/or aspirin treatment and beginning of reversible
short-acting P2Y.sub.12 inhibitor. Such dosing regime can also
ensure a constant level of platelet activity inhibition.
[0057] In other forms, a reversible, short-acting P2Y.sub.12
inhibitor can be administered at a daily dose of from 0.1 mg to
1000 mg, which may be in divided doses, e.g., up to 6 times per
day.
[0058] The total amount of reversible, short-acting P2Y.sub.12
inhibitor that may be administered to a subject may be between
about 0.01 and 1000 mg per 24 hour period, with exemplary totals of
about 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 and 2.5 mg per 24 hour
period.
[0059] In each of the embodiments where the pharmaceutical
composition is administered as continuous intravenous infusion, the
infusion may continue for at least about 2 days to about 7 days.
The skilled artisan will understand that the period of time over
which the pharmaceutical composition is administered may be shorter
or longer than the indicated times due to the particular
characteristics of a patient. Administration of a reversible,
short-acting P2Y.sub.12 inhibitor can be made several days to
several hours prior to the invasive procedure. One example is to
administer a reversible, short-acting P2Y.sub.12 inhibitor about 7
days to about 1 hour prior to an invasive procedure. To maintain
platelet inhibition, the reversible short-acting P2Y.sub.12
inhibitor should be administered within about 2 days to about 7
days of ceasing administration of the long-acting platelet
inhibitor. A further example is to administer the reversible
short-acting P2Y.sub.12 inhibitor within about 3 days of ceasing
administration of the long-acting platelet inhibitor.
Discontinuation of the reversible short-acting P2Y.sub.12 inhibitor
can be performed about 1 to 6 hours before a surgical procedure. It
should be noted that the duration for administering a reversible,
short-acting P2Y.sub.12 inhibitor often vary depending on which
reversible, short-acting P2Y.sub.12 inhibitor is used and the
particular characteristic of the patient. One skilled in the art
can vary the duration of administration so long as platelet
inhibition as measured by VerifyNow.RTM. is below about 240.
[0060] Reversible, short-acting P2Y.sub.12 inhibitors, such as
cangrelor, ticagrelor or PRT060128, can be administered using any
of the various methods and delivery systems known to those skilled
in the art. The administering can be performed, for example,
intravenously, orally, via implant, transmucosally, transdermally,
intramuscularly, intrathecally, and subcutaneously. According to
one preferred embodiment, a reversible, short-acting P2Y.sub.12
inhibitor may be administered intravenously. It is contemplated
that the reversible, short-acting P2Y.sub.12 inhibitor can be
administered intravenously in accordance with the present invention
during surgery, when the patient is comatose, or any other such
scenario where the oral administration of the inhibitor is
prohibited.
[0061] In the case of administering the therapy prior to surgery in
accordance with one embodiment of the present invention, such use
allows patients to undergo surgery or other invasive procedures
without excessive perioperative bleeding. For example, as described
herein, cangrelor infusion can maintain platelet inhibition levels
of approximately greater than or equal to about 60% after
discontinuation of clopidogrel without an increase in bleeding risk
and before the invasive procedure begins.
[0062] In addition to the pharmaceutical compositions of the
present invention comprising cangrelor, the skilled artisan will
understand that additional therapeutic agents may be used in
combination with cangrelor. By way of non-limiting examples,
compounds such as aspirin, bivalirudin, unfractionated heparin, low
molecular weight heparin, fondaprinux sodium, warfarin, coumarins,
thrombolytics such as streptokinase, alteplase, reteplase,
urokinse, tenecteplase, glycoprotein IIb/IIIa inhibitors such as
eptifibatide, abciximab, tirofiban, or antifibrinolytic agents such
as epsilon amino-caproic acid, and tranexamic acid, can be used as
concomitant medications.
[0063] Measurement of Platelet Activity
[0064] Assessment of platelet function can be determined by use of
the VerifyNow.RTM. assay of which the System User Manual
(Accumetrics, San Diego, Calif., 2009) is incorporated by reference
in its entirety. The VerifyNow.RTM. P2Y12 assay is a point of care
device for the assessment of the level of inhibition of platelet
activation specifically designed for patients exposed to
thienopyridines. It should be understood that any assay system for
determining levels of inhibition of platelet activation can be
used, as understood by those having skill in the art. Blood samples
for the VerifyNow.RTM. P2Y12 assay can be collected into Greiner
Bio-One Vacuette partial fill blood collection tubes (2 mL fill
volume) containing 3.2% citrate, or by other suitable means.
[0065] The VerifyNow.RTM. P2Y12 assay is a rapid platelet-function
cartridge-based assay that activates platelets using adenosine
diphosphate (ADP), but also uses prostaglandin E1 to suppress the
ADP-induced P2Y1-mediated increase in intracellular calcium levels
to increase the specificity of the test for inhibition of the
P2Y.sub.12 receptor. The test cartridge contains a lyophilized
preparation of human fibrinogen coated beads, platelet agonist,
buffer and preservative. Fibrinogen-coated microparticles are used
to bind to available platelet receptors. When the activated
platelets are exposed to the fibrinogen-coated microparticles,
agglutination occurs in proportion to the number of available
platelet receptors. The whole-blood citrate mixture is added to the
cartridge, and agglutination between platelets and coated beads is
recorded. The VerifyNow.RTM. P2Y12 device is a turbidimetric
optical detection system, which measures platelet induced
aggregation as an increase in light transmittance. VerifyNow.RTM.
P2Y12 testing can be used at any time point as described herein to
assess the level of inhibition of platelet activity.
[0066] Assay results are expressed in P2Y12 reaction units (PRU)
(VerifyNow.RTM. System User Manual (Accumetrics, San Diego, Calif.,
2009)). High platelet reactivity, as assessed by VerifyNow.RTM.
P2Y12 assay was defined as a PRU value greater than 240. The lower
the PRU value, the greater the inhibition of the P2Y.sub.12
receptor resulting in reduction of the platelet activity. For the
methods described in this invention, the PRU level is preferably
maintained during the period of cangrelor administration at 240 or
less. In a preferred embodiment of the present invention, the dose
of cangrelor was 0.75 .mu.g/kg/min. This dose was maintained for
about 2 to about 7 days. PRU values in the patients were less than
or equal to 240.
[0067] It would be understood by those skilled in the art that
increasing the concentration of cangrelor infusion will result in a
decrease in PRU values and an increase in the percent platelet
inhibition. It is therefore preferred to measure PRU values during
the course of cangrelor infusion.
[0068] Pharmaceutical Compositions
[0069] In each aspect and embodiment of the present invention,
short-acting reversible platelet inhibitor is administered to a
patient in the form of a pharmaceutical composition comprising the
active ingredient and, optionally, a pharmaceutically acceptable
carrier, diluent and/or excipient. Thus, the present invention
encompasses a pharmaceutical composition comprising cangrelor, and
a pharmaceutically acceptable carrier, diluent and/or
excipient.
[0070] Suitable carriers and diluents are well known to those
skilled in the art and include saline, such as 0.9% NaCl, buffered
saline, dextrose (e.g., 5% dextrose in water), water,
Water-for-Injection (WFI), glycerol, ethanol, ringer's solution,
propylene glycol, polysorbate 80 (Tween-80), 0.002% polysorbate 80
(Tween-80), poly(ethylene)glycol 300 and 400 (PEG 300 and 400),
PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188, a
cyclodextrin or a cyclodextrin derivative (including HPCD
((2-hydroxypropyl)-cyclodextrin) and (2-hydroxyethyl)-cyclodextrin,
hydrophilic and hydrophobic carriers, and combinations thereof.
Hydrophobic carriers include, for example, fat emulsions, lipids,
PEGylated phospholipids, polymer matrices, biocompatible polymers,
lipospheres, vesicles, particles, and liposomes. Excipients
included in a pharmaceutical composition have different purposes
depending, for example, on the nature of the drugs, and the mode of
administration. Examples of generally used excipients include,
without limitation: stabilizing agents, solubilizing agents and
surfactants, buffers, antioxidants and preservatives, tonicity
agents, bulking agents, lubricating agents, emulsifiers, suspending
or viscosity agents, inert diluents, fillers, disintegrating
agents, binding agents, wetting agents, lubricating agents,
antibacterials, chelating agents, sweeteners, perfuming agents,
flavouring agents, coloring agents, administration aids, and
combinations thereof.
[0071] The pharmaceutical composition may contain common carriers
and excipients, such as cornstarch or gelatin, lactose, sucrose,
microcrystalline cellulose, kaolin, mannitol, sorbiton, dicalcium
phosphate, sodium chloride, alginic acid, croscarmellose sodium,
and sodium starch glycolate.
[0072] The pharmaceutical compositions of the present invention may
be formulated, for example, for oral, sublingual, intranasal,
intraocular, rectal, transdermal, mucosal, topical or parenteral
administration. Parenteral modes of administration include without
limitation, intradermal, subcutaneous (s.c., s.q., sub-Q, Hypo),
intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.),
intra-arterial, intramedulary, intracardiac, intra-articular
(joint), intrasynovial (joint fluid area), intracranial,
intraspinal, and intrathecal (spinal fluids). Any known device
useful for parenteral injection or infusion of drug formulations
can be used to effect such administration. In noted aspects and
embodiments of the present invention, administration of the
pharmaceutical compositions is via parenteral administration,
preferably intravenous administration.
[0073] In intravenous (IV) administration, a sterile formulation of
the pharmaceutical compositions of the present invention and
optionally one or more additives, including solubilizers or
surfactants, can be dissolved or suspended in any of the commonly
used intravenous fluids and administered by infusion. Intravenous
fluids include, without limitation, isotonic infusion media such as
physiological saline, 0.9% NaCl, phosphate buffered saline, 5%
dextrose in water, 0.002% polysorbate 80 (Tween-80) in water or
Ringer's solution.
[0074] Pharmaceutical compositions comprising cangrelor of the
present invention include pharmaceutical compositions comprising
from about 0.1 to about 50 mg/ml of cangrelor. Particular examples
of pharmaceutical compositions comprising cangrelor include the
following: (i) cangrelor at a concentration of about 0.1, 0.5, 1,
2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/mL in 0.9% NaCl; and (ii)
cangrelor at a concentration of about 0.1, 0.5, 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10 mg/mL in 5% dextrose in water. The pharmaceutical
composition may further comprise a pharmaceutically acceptable
carrier or diluent such as sorbitol and mannitol.
[0075] One method for preparing a cangrelor composition includes
dissolving 50 mg lyophilized cangrelor or its pharmaceutically
acceptable salt by injecting 5 ml sterile water into a 10 ml vial
containing cangrelor or its pharmaceutically acceptable salt
thereof, preparing an intravenous bag by immediately adding the
dissolved cangrelor to an intravenous bag containing saline
solution in volumes such as 250 ml, 500 ml, or 1000 ml of saline
solution and mixing the intravenous bag thoroughly for
administration. Cangrelor compositions should be prepared
immediately prior to administration via infusion. It is within the
skilled in the art to vary the volume of saline and amount of
cangrelor in the exemplary method described above to achieve the
dosage amount described in the preferred embodiments.
[0076] The described methods can be used for patients diagnosed
with symptoms of conditions such as stable or unstable angina,
vascular ischemic events, atherosclerosis, acute coronary syndrome,
including STEMI or N-STEMI. The described methods can also be used
for patients having previously received a stent, such as a bare
metal stent or a drug-eluting stent, and the treatment or
prevention of stent thrombosis.
[0077] The described methods can be used for a patient before,
during, and after an invasive procedure, such as coronary artery
bypass grafting, orthopedic surgeries, urological surgeries,
percutaneous coronary intervention, other general invasive
procedures, such as endarterectomy, renal dialysis,
cardio-pulmonary bypass, endoscopic procedures or any medical,
surgical, or dental procedure that could potentially lead to
excessive bleeding or hemorrhage.
[0078] Further, the described methods of the present invention can
be used in a patient who cannot be orally administered therapies
and, for whatever reason, cannot be administered long lasting
thienopyridines, such as clopidogrel or Plavix.RTM..
[0079] Results of the Methods
[0080] To determine how to administer a reversible, short-acting
P2Y.sub.12 inhibitor or the amount of a reversible, short-acting
P2Y.sub.12 inhibitor to be administered, the pharmacokinetic
profile of the reversible, short-acting P2Y.sub.12 inhibitor can be
analyzed using the methods well-known to a person skilled in the
art.
[0081] For example, the pharmacokinetics of cangrelor has been
shown to be substantially linear, and its steady-state plasma
concentrations can be achieved in less than approximately 5 minutes
following the administration of an intravenous infusion.
[0082] Cangrelor produced potent inhibition of ADP-induced platelet
aggregation ex vivo with IC50 7.72+/-1.95 ng/mL. As may be seen in
FIG. 1, over 80% inhibition was achieved at doses of about 0.5
.mu.g/kg/min and above. Inhibition by cangrelor was rapidly
reversible and platelet aggregation response restored close to
baseline within one hour of stopping the infusion. An infusion dose
of approximately about 0.75 .mu.g/kg/min of cangrelor can also
maintain adequate antiplatelet activity during infusion in the
targeted patient prior to an invasive procedure.
[0083] It has been determined that consistent and complete platelet
inhibition can be maintained throughout cangrelor infusion with
full recovery of platelet function within approximately one hour of
infusion cessation. Clopidogrel administration at the termination
of cangrelor infusion may lead to the expected degree of platelet
inhibition, which may be measured by P-selectin expression,
electrical impedance and light transmittance aggregometry.
[0084] Transition from PCI Dosing Regimen to Bridge Dosing Regimen,
and from Bridge Dosing Regimen to PCI Dosing Regimen
[0085] An aspect of the present invention is a method of
transitioning a patient from administration of cangrelor during PCI
to administration of cangrelor in preparation for surgery, or a
method of transitioning a patient from administration of cangrelor
in preparation for surgery to administration of cangrelor during
PCI. Another aspect of the invention is a method of maintaining
reduced platelet activity in a patient who is transitioning from
administration of cangrelor during PCI to administration of
cangrelor in preparation for surgery, or who is transitioning from
administration of cangrelor in preparation for surgery to
administration of cangrelor during PCI. Yet a further aspect of the
invention is a method of maintaining P2Y.sub.12 inhibition in a
patient who is transitioning from administration of cangrelor
during PCI to administration of cangrelor in preparation for
surgery, or who is transitioning from administration of cangrelor
in preparation for surgery to administration of cangrelor during
PCI.
[0086] The reasons why a patient may have to transition from
administration of cangrelor during PCI to administration of
cangrelor in preparation for surgery, or vice-versa, can vary. For
example, as a patient is administered cangrelor during PCI, it may
be determined that surgery is necessary due to, for instance, new
information that was gathered during PCI or complications that
arose from the PCI procedure itself. On the other hand, a patient
administered cangrelor during preparation for surgery may have to
undergo PCI, such as when it is discovered that the patient is in
immediate need of angioplasty or the implantation of a stent. In
each of these cases, the patient has to change from one dosing
regimen of cangrelor to a different dosing regimen.
[0087] Transitioning from administration of cangrelor during PCI to
administration of cangrelor in preparation for surgery may be
performed by administering a PCI dosing regimen, discontinuing the
administration of the PCI dosing regimen, and administering a
bridge dosing regimen. Transitioning from administration of
cangrelor in preparation for surgery to administration of cangrelor
during PCI may be performed by administering a bridge dosing
regimen, discontinuing the administration of the bridge dosing
regimen, and administering a PCI dosing regimen. A "PCI dosing
regimen" refers to the doses of cangrelor that a patient receives
when undergoing PCI. A "bridge dosing regimen" refers to the doses
of cangrelor that a patient receives in the "bridging" period
leading up to surgery, i.e., the period of time between the
discontinuation of oral P2Y.sub.12 inhibitors and surgery.
[0088] The PCI dosing regimen comprises administering intravenously
a continuous infusion of cangrelor at a rate of about 3 to about 10
.mu.g/kg/min, or about 4 .mu.g/kg/min. The continuous infusion may
be accompanied by intravenous administration of a bolus. The bolus
may comprise about 10 to about 100 .mu.g/kg cangrelor, such as
between about 20 and about 40 .mu.g/kg cangrelor, or about 30
.mu.g/kg cangrelor. The bolus may be administered rapidly, for
example, in less than about two minutes, or less than about one
minute. Preferably, the administration of the continuous infusion
is started immediately after the administration of the bolus.
[0089] The bridge dosing regimen comprises administering
intravenously a continuous infusion of cangrelor at a rate of about
0.1 to about 2 .mu.g/kg/min, or about 0.75 .mu.g/kg/min.
[0090] The cangrelor may be administered in a pharmaceutical
composition. The pharmaceutical composition may comprise 200
.mu.g/mL of cangrelor. The pharmaceutical composition may also
comprise sodium chloride injection 0.9% USP or 5% dextrose
injection, USP.
[0091] In embodiments in which the patient is transitioning from
administration of cangrelor during PCI to administration of
cangrelor in preparation for surgery, the discontinuation of the
administration of the PCI dosing regimen may occur at any time
during the PCI continuous infusion. The administration of the
bridge dosing regimen may occur as quickly as possible following
the discontinuation of the administration of the PCI dosing
regimen. In some embodiments, the discontinuation of the
administration of the PCI dosing regimen and the administration of
the bridge dosing regimen may be achieved simultaneously by
lowering the PCI continuous infusion rate to the bridge continuous
infusion rate. The administration of the bridge dosing regimen may
be discontinued at least about one hour prior to administration of
anesthesia for the surgery. Moreover, the administration of the
bridge dosing regimen may be discontinued after no longer than
about 7 days from initiation.
[0092] In embodiments in which the patient is transitioning from
administration of cangrelor in preparation of surgery to
administration of cangrelor during PCI, the discontinuation of the
administration of the bridge dosing regimen can occur any time
during the bridge continuous infusion. The administration of the
PCI dosing regimen may occur as quickly as possible following the
discontinuation of the administration of the bridge dosing regimen.
In some embodiments, the discontinuation of the administration of
the bridge dosing regimen and the administration of the PCI dosing
regimen may be achieved simultaneously by increasing the bridge
continuous infusion rate to the PCI continuous infusion rate. If
the PCI dosing regimen includes the administration of a bolus, then
the bolus can be administered immediately before or after the
increase to the PCI continuous infusion rate. The administration of
the continuous infusion of cangrelor in PCI dosing regimen may
continue for the longer of (a) at least two hours, or (b) the
duration of PCI. The continuous infusion may be continued for a
total duration of about four hours.
EXAMPLES
Example 1
[0093] Without limitations, FIG. 2 provides a brief summary as to
how the methods described in the present invention may be used in a
patient in need thereof. It should be understood that the method of
the present invention is not limited to the procedure described in
FIG. 2.
[0094] FIG. 2, shows a screening period 210 used for determining
the dosage necessary for achieving platelet inhibition greater than
a pre-determined level, for example, of approximately 60%. A
pre-operative period 220 of up to approximately 7 days prior to
surgery can be used for administration of a reversible,
short-acting P2Y.sub.12 inhibitor. An intra-operative period 230
lasting from the discontinuation of the reversible, short-acting
P2Y.sub.12 inhibitor to the end of surgery can be used.
[0095] During the screening period 210, the dosage of a reversible,
short-acting P2Y.sub.12 inhibitor, necessary to achieve platelet
inhibition greater than approximately 60% can be determined. Other
suitable levels of percent inhibition are approximately 65, 70, 75,
80, 85, 90, 95 and 100%. For example, intravenous infusion of a
reversible, short-acting P2Y.sub.12 inhibitor can be administered
to a patient in doses typically ranging from about 0.5 .mu.g/kg/min
to about 5.0 .mu.g/kg/min, preferably about 0.5 .mu.g/kg/min to
about 2.0 .mu.g/kg/min and particularly at doses of 0.5
.mu.g/kg/min, 0.75 .mu.g/kg/min, 1.0 .mu.g/kg/min, 1.5 .mu.g/kg/min
and 2.0 .mu.g/kg/min, until measured platelet inhibition is greater
than the pre-determined level. Smaller or larger doses may also be
used as needed to achieve the required level of platelet
inhibition.
[0096] Optionally, the dosage of a reversible, short-acting
P2Y.sub.12 inhibitor for any particular patient can also be
determined ahead of time, so as to reduce the need to give multiple
doses to achieve the required level of platelet inhibition. In all
instances where measurement of platelet inhibition is needed, a
baseline value should be obtained to accurately determine when
acceptable levels have been reached.
[0097] During pre-operative period 220, administration of a
reversible, short-acting P2Y.sub.12 inhibitor can be initiated the
day the decision is made to discontinue the long-acting
irreversible platelet inhibitor and may be continued throughout
pre-operative period 220. In another embodiment, administration of
cangrelor can be made within 3 days of ceasing administration of
the long-acting irreversible platelet inhibitor.
[0098] A patient can undergo CABG within 3 days of ceasing
administration of the long-acting irreversible platelet inhibitor.
The dose of such a reversible, short-acting P2Y.sub.12 inhibitor
can remain constant or can be periodic during the treatment period.
Preferably the dosage of cangrelor remains continuous during the
treatment period of about 2 to about 7 days. Treatment with
reversible, short-acting P2Y.sub.12 inhibitor may then be
terminated from about one hour to about 6 hours before an invasive
procedure.
[0099] Also during pre-operative period 220, any number of
procedures and/or tests can be performed in conjunction with the
present invention, such as hemoglobin, hematocrit, white blood
cells, and platelet count testing; serum creatinine testing;
measurement of inhibition of platelet activation; and assessment of
concomitant medications, adverse events, serious adverse events and
other various clinical endpoints. Additionally, procedures such as
CK and CK-MB and VerifyNow.RTM. P2Y12 assays, for example, can be
performed within 24 hours prior to surgery.
[0100] During intra-operative period 230, administration of a
reversible, short-acting P2Y.sub.12 inhibitor can be stopped
between from about at least 1 hour and up to approximately 3 hours
prior to administration of anesthesia for surgery. Basic standard
of care treatment is used for the surgical period as understood by
those having skill in the art. Collection of concomitant
medications and assessments of adverse events, serious adverse
events and clinical endpoints can also be performed during this
period as needed.
Example 2
[0101] FIG. 3 describes a non-limiting exemplary method for
maintaining or reducing platelet activity in patients who were
previously treated with thienopyridine prior to undergoing an
invasive procedure such as CABG.
[0102] In FIG. 3, a total of 207 patients were studied. Patients
were included in this study if they met all of the following
criteria: (1) Must be at least 18 years of age; (2) Anticipate
non-emergent coronary artery bypass graft (CABG) surgery, either
"on-pump" or "off-pump," no sooner than 48 hours from randomization
but no longer than 7 days from randomization, with patient to
remain hospitalized until planned CABG; and (3) Have received a
thienopyridine (at least 75 mg of clopidogrel, 500 mg ticlopidine,
or 10 mg prasugrel) within 72 hours prior to enrollment in the
study for either the treatment of an acute coronary syndrome,
regardless of time from ACS, and/or as long-term preventative
therapy following drug-eluting or bare metal stent treatment.
[0103] Patients were excluded from the study if any of the
following exclusion criteria applied prior to randomization: (1)
Confirmed or suspected pregnancy (if woman of child-bearing
potential) or lactating females; (2) Cerebrovascular accident
within one year; (3) Intracranial neoplasm or history of
intracranial surgery; (4) History of bleeding diathesis; (5)
Thrombocytopenia (platelet count of less than 100,000/.mu.L); (6)
Known International Normalized Ratio (INR) greater than 1.5 at
screening; (7) Requirement for dialysis treatment (hemodialysis or
peritoneal); (8) Estimated Glomeular filtration rate eGFR<30
ml/min; (9) Administration of abciximab within 24 hours of
randomization or administration of eptifibitide or tirofiban within
12 hours of randomization; (10) Plans to continue oral
anticoagulant, thienopyridine or GPIIb/IIIa antagonist therapy in
the pre-operative period; (11) Known or suspected coagulopathy;
(12) Refusal to receive blood transfusion; (13) Receipt of
fibrinolytic therapy in the 12 hours preceding randomization; (14)
Allergy, hypersensitivity, or contraindication to cangrelor,
mannitol, sorbitol, or microcrystalline cellulose; (15) High
likelihood of being unavailable for follow-up; (16) Participation
in other studies involving the evaluation of other investigational
drugs or devices within 30 days of randomization; or (17) Any
disease or condition which, in the judgment of the health care
provider, would place the patient at undue risk by participating in
the study.
[0104] Patients were randomized into two groups, a cangrelor plus
standard of care (SOC) group, and a placebo plus SOC group. A dose
study was performed, for cangrelor plus SOC and placebo plus SOC
respectively. A dose of 0.75 .mu.g/kg/min was confirmed for the
cangrelor plus SOC and placebo plus SOC groups.
[0105] In the placebo plus SOC group, patients received only SOC,
in which the thienopyridine is discontinued after the need for
surgery had been determined and a placebo infusion is administered.
In the cangrelor plus standard of care (SOC) group, a cangrelor
infusion was started in addition to SOC when the thienopyridine was
discontinued after the need for surgery had been determined. The
infusions (cangrelor or matching placebo) were continued throughout
the pre-operative period. Patients can wait 5 days after
discontinuation of clopidogrel before undergoing surgery but the
timing of surgery can vary and be left to the discretion of the
health care practitioner with a maximum of 7 days of cangrelor
infusion.
[0106] Daily measurements of platelet inhibition were taken using
the VerifyNow.RTM. P2Y12 assay system.
[0107] All patients randomized receive SOC and waited up to five
days after discontinuation of thienopyridine before undergoing
CABG. Antiplatelet therapy with aspirin was maintained during this
time. Anti-thrombotics such as unfractionated heparin and
enoxaparin were allowed and given at the discretion of the health
care provider. It was recommended that enoxaparin be
discontinued>24 hours before CABG although concomitant use of
other antiplatelet and anti-thrombic agents is contemplated by the
invention described here. It was recognized that clinical events
may occur leading to surgery before the 5 day waiting period is
completed and therefore the decision to proceed to surgery was left
to the discretion of the health care provider.
[0108] For patients randomized to the cangrelor arm, cangrelor
infusion was started as quickly as possible and no more than 6
hours after randomization. Patients received an infusion of
cangrelor, in addition to their SOC therapy, at a rate of 0.75
.mu.g/kg/min.
[0109] Cangrelor was infused continuously via a dedicated
peripheral or central line for at least about 2 days and up to
about 7 days. The dose of cangrelor remained constant during the
infusion period. The cangrelor infusion was terminated at least one
and no more than six hours before induction of anesthesia for the
scheduled CABG surgery. Induction of anesthesia is defined as the
start time of IV anesthesia. Patients were infused with cangrelor
for a minimum of 48 hours prior to termination.
[0110] Patients not randomized to receive cangrelor received a
placebo infusion administered in the same manner as the cangrelor
infusion in addition to their SOC therapy.
[0111] FIGS. 4-1 and 4-2 include a table that summarizes the study
assessments by time point. This study consisted of 5 periods: (1)
Screening/Randomization Period, (2) Pre-operative (Days 1-7 defined
as the period from randomization to discontinuation of cangrelor),
(3) Intra-operative (from discontinuation of cangrelor to end of
CABG surgery), (4) Post-operative Follow-up (from end of CABG
surgery to hospital discharge), and (5) 30-Day Follow-up (30+5 days
from time of CABG).
[0112] Pre-operative Period (Randomization until discontinuation of
cangrelor): Just prior to the administration of cangrelor, a
VerifyNow.RTM. P2Y12 Assay was performed to obtain a baseline
assessment. Testing was performed irrespective of the timing of
last dose of thienopyridine received. Immediately following the
VerifyNow.RTM. P2Y12 Assay, the cangrelor composition was prepared
and an infusion at the rate of 0.75 .mu.g/kg/min was started. This
infusion was maintained until 1 to 6 hours prior to anesthesia
administration for the CABG surgery. The following tests were
performed daily, at approximately the same time, during all days of
cangrelor infusion: Hematology labs [hemoglobin, hematocrit, white
blood cells (WBC), and platelet count] PRU and percent platelet
inhibition determined by VerifyNow.RTM. P2Y12 Assay Assessment of
concomitant medications. Within 12 hours prior to surgery, the
following procedures were conducted: Additional VerifyNow.RTM.
P2Y12 assay just prior to cangrelor termination. If the last
on-infusion VerifyNow.RTM. sample was within 12 hours of cangrelor
discontinuation, an additional draw was not required prior to
termination of cangrelor.
[0113] Table 1 below represents the results of cangrelor and
placebo treatment during the pre-operative period.
TABLE-US-00001 TABLE 1 Summary of PRU by Day Cangrelor Placebo Stat
(N = 93) (N = 90) Screening: Patients w/PRU <240 n/N (%) 53/85
(62.4) 45/86 (52.3) PRU N 85 86 MEAN .+-. SD 210.9 .+-. 94.0 214.1
.+-. 85.9 MEDIAN 201.0 233.5 (Q1, Q3) 166, 280 151, 279 (MIN, MAX)
3, 418 10, 395 Day 1 sample Patients w/PRU <240 n/N (%) 80/80
(100) 34/76 (44.7) PRU N 80 76 MEAN .+-. SD 45.5 .+-. 47.1 232.7
.+-. 74.2 MEDIAN 31.0 249.0 (Q1, Q3) 5, 78 178, 287 (MIN, MAX) 0,
169 47, 367 Day 2 sample: Patients w/PRU <240 n/N (%) 69/70
(98.6) 25/73 (34.2) PRU N 70 73 MEAN .+-. SD 58.8 .+-. 58.1 239.2
.+-. 71.1 MEDIAN 40.0 256.0 (Q1, Q3) 6, 100 218, 282 (MIN, MAX) 0,
271 64, 354 Day 3 sample: Patients w/PRU <240 n/N (%) 55/55
(100) 21/57 (36.8) PRU N 55 57 MEAN .+-. SD 69.2 .+-. 59.8 250.4
.+-. 64.7 MEDIAN 52.0 263.0 (Q1, Q3) 8, 117 200, 306 (MIN, MAX) 0,
229 105, 358 Day 4 sample: Patients w/PRU <240 n/N (%) 33/33
(100) 7/34 (20.6) PRU N 33 34 MEAN .+-. SD 80.3 .+-. 61.7 286.5
.+-. 65.5 MEDIAN 78.0 296.0 (Q1, Q3) 33, 115 241, 344 (MIN, MAX) 1,
219 118, 406 Day 5 sample: Patients w/PRU <240 n/N (%) 7/7 (100)
6/24 (25.0) PRU N 7 24 MEAN .+-. SD 52.1 .+-. 58.1 284.0 .+-. 64.0
MEDIAN 30.0 285.5 (Q1, Q3) 9, 117 244, 328 (MIN, MAX) 7, 151 140,
388 Day 6 sample: Patients w/PRU <240 n/N (%) 6/6 (100) 3/14
(21.4) PRU N 6 14 MEAN .+-. SD 62.7 .+-. 74.7 291.3 .+-. 54.1
MEDIAN 45.5 280.0 (Q1, Q3) 9, 67 250, 329 (MIN, MAX) 3, 206 217,
399 Day 7 sample: Patients w/PRU <240 n/N (%) 1/1 (100) 0/2
(0.0) PRU N 1 2 MEAN .+-. SD 3.0 .+-. . 343.5 .+-. 4.9 MEDIAN 3.0
343.5 (Q1, Q3) 3, 3 340, 347 (MIN, MAX) 3, 3 340, 347 Last
on-treatment sample: Patients w/PRU <240 n/N (%) 83/84 (98.8)
26/84 (31.0) PRU N 84 84 MEAN .+-. SD 68.9 .+-. 67.8 263.7 .+-.
68.3 MEDIAN 53.0 263.5 (Q1, Q3) 8, 110 227, 311 (MIN, MAX) 0, 271
81, 399 Last post-treatment pre-CABG: Patients w/PRU <240 n/N
(%) 21/78 (26.9) 15/75 (20.0) PRU N 78 75 MEAN .+-. SD 279.7 .+-.
106.5 297.8 .+-. 67.3 MEDIAN 293.0 299.0 (Q1, Q3) 228, 357 256, 345
(MIN, MAX) 1, 471 144, 445
[0114] The data in Table 1 indicates that infusion of Cangrelor at
a dose of 0.75 .mu.g/kg/min between day 1 to day 7 maintains PRU
values below 240 in over 90% of the patients studied. The table
further indicates that for the "last post-treatment pre-CABG" where
cangrelor infusion is terminated but prior to CABG, the level of
PRU has resumed to levels prior to cangrelor treatment.
[0115] Intra-operative Period (Period from discontinuation of
cangrelor until end of CABG surgery): The Intra-operative period
started at termination of cangrelor infusion (surgery start is
defined as time of first incision). Cangrelor infusion was stopped
at least 1 hour and a maximum of 6 hours prior to administration of
anesthesia for surgery. Standard of care treatment was used for the
surgical period. Collection of the following assessments were
conducted during this period: (i) serum creatinine and
LFTs--following discontinuation of cangrelor but prior to surgery
(surgery start time is defined as the time of first surgical
incision); (ii) VerifyNow.RTM. P2Y12 assay just prior to first
surgical incision; and (iii) concomitant medications and
assessments of adverse events, serious adverse events and clinical
endpoints.
[0116] In the case of administering and ceasing the therapy prior
to surgery in accordance with one embodiment of the present
invention, such use allows patients to undergo surgery or other
invasive procedures without excessive perioperative bleeding.
[0117] Table 2 represents the bleeding risks associated with
cangrelor and placebo treatment.
TABLE-US-00002 TABLE 2 Summary of CABG Related Bleeding During the
CABP Procedure through Hospital Discharge Cangrelor Placebo Stat (N
= 106) (N = 101) CABG related bleeding n/N (%) 10/102 (9.8) 10/96
(10.4) Fatal bleeding n/N (%) 0 0 Periop. intracranial n/N (%) 0 0
bleeding Re operation for n/N (%) 2/102 (2.0) 2/96 (2.1) bleeding
Whole Blood or n/N (%) 7/102 (6.9) 8/96 (8.3) pRBC Transfusion
>=5 units 24 hour CT output n/N (%) 3/102 (2.9) 4/96 (4.2)
>=2 L
[0118] The results of Table 2 indicates that bleeding risk
associated with cangrelor treatment is the same as or similar to
treatment with placebo.
[0119] Table 3 represents the overall incidence of ischemic
events
TABLE-US-00003 TABLE 3 Overall Incidence of Ischemic Events
Cangrelor Placebo Stat (N = 106) (N = 101) Pre-procedure
Death/MI/IDR/Stroke n/N (%) 3/106 (2.8) 4/101 (4.0) Death n/N (%)
1/106 (0.9) 3/101 (3.0) MI n/N (%) 2/106 (1.9) 0/101 (0.0) IDR n/N
(%) 1/106 (0.9) 0/101 (0.0) Stroke n/N (%) 0/106 (0.0) 1/101 (1.0)
Post-procedure Death/MI/IDR/Stroke n/N (%) 4/102 (3.9) 4/96 (4.2)
Death n/N (%) 1/102 (1.0) 2/96 (2.1) MI n/N (%) 2/102 (2.0) 1/96
(1.0) IDR n/N (%) 2/102 (2.0) 0/96 (0.0) Stroke n/N (%) 1/102 (1.0)
1/96 (1.0) Pre and Post-procedures Death/MI/IDR/Stroke n/N (%)
10/106 (9.4) 8/101 (7.9) Death n/N (%) 2/106 (1.9) 5/101 (5.0) MI
n/N (%) 4/106 (3.8) 1/101 (1.0) IDR n/N (%) 6/106 (5.7) 0/101 (0.0)
Stroke n/N (%) 1/106 (0.9) 2/101 (2.0)
[0120] The results of Table 3 indicate that the ischemic events
relating to the methods described herein with the use of cangrelor
are comparable to the placebo.
[0121] Post-operative Period (Period from end of CABG surgery to
hospital discharge): The following procedures were performed
following surgery (end of CABG surgery is defined as the placement
of the last suture): VerifyNow.RTM. P2Y12 Assay was performed
within 1 hour following surgery Hematology labs, 12 lead-ECG and
VerifyNow.RTM. P2Y12 Assay were performed 24-hours (.+-.1 h)
following surgery. Chest tube output will be assessed at 4 hours
(.+-.1 h) and 24 hours (.+-.1 h) following surgery.
Example 3
[0122] In another example and in accordance with one embodiment of
the present invention, the administration of the at least one
reversible, short-acting P2Y.sub.12 inhibitor occurs during an
invasive procedure being performed on the subject. In this manner,
it is contemplated that the administration of the inhibitor would
occur intravenously as the subject cannot take the therapy
orally.
Example 4a
[0123] In another example and in accordance with another embodiment
of the present invention, the administration of the at least one
reversible, short-acting P2Y.sub.12 inhibitor occurs after an
invasive procedure has been performed on the subject. The
administration of the inhibitor in the post surgery scenario can
occur in a variety of methods as described above. It is
contemplated that the administration of the inhibitor may also
occur intravenously post surgery if the subject cannot take the
therapy orally, for example, if the subject is comatose.
Example 4b
[0124] The study for using cangrelor in early post-operative
period:
[0125] Current standard of care for antiplatelet maintenance
therapy after PCI in patients with implanted stents is based on
recommendations of the American College of Cardiology/American
Heart Association (ACC/AHA) guidelines (Fleisher L A, et al.,
ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation
and care for noncardiac surgery: a report of the ACC/AHA Task Force
on Practice Guidelines. Circulation. 2007 Oct. 23; 116(17):
e418-99) that suggest an early initiation of dual antiplatelet
therapy and continuation of maintenance therapy with aspirin and
clopidogrel after PCI from 6 to 12 months, depending on the stent
type, in order to prevent post-procedural stent thrombosis. Both
aspirin and clopidogrel are irreversible platelet antagonists,
therefore ACC/AHA guidelines recommend cessation of clopidogrel
before non-emergent surgical procedures in order to minimize
bleeding risks.
[0126] However, should patients with implanted stents require a
surgical procedure, early cessation of clopidogrel would increase
the risk for ischemic events and stent thrombosis (Berger et al.,
Circulation. 2002 Oct. 22; 106(17): 2284-7; Ho et al. JAMA. 2008
Feb. 6; 299(5): 532-9). Conversely, maintaining irreversible
platelet inhibition with aspirin and clopidogrel leads to
unacceptable operative bleeding risk (Fox et al., Circulation.
2004; 110: 1202-1208; Shim et al., J Thorac Cardiovasc Surg. 2007
July; 134(1): 59-64; Pickard et al., Pharmacotherapy. 2008 March;
28(3): 376-92. Review).
[0127] Because of the risk of bleeding from the surgical sites,
surgeons prefer to avoid using anticoagulant agents in early
post-operative period especially with irreversible oral therapy
that will not allow predicting the level of platelet inhibition and
fast recovery of platelet function when surgical procedure could be
associated with high risk of post-operative bleeding.
[0128] It is well known that surgical interventions trigger
platelet activation and aggregation, hence increasing the risk of
stent thrombosis in post-operative period if patient do not
continue antiplatelet therapy.
[0129] It has been demonstrated in several studies that early
initiation of anticoagulant therapy may diminish the risk of venous
thrombosis (Segers A. J Thromb Haemost. 2008 August; 6(8): 1313-8;
Turpie et al., Lancet. 2009 May 1), however there is no consensus
or standard antiplatelet therapy regimen designed to reduce the
risk of arterial stent thrombosis in patients with implanted stents
requiring surgical procedures.
[0130] Typically, at conclusion of surgical procedure a complete
hemostasis is achieved, however, the risk of bleeding from the
surgical site remains high during the first post-operative hours.
Initiation of antiplatelet therapy during the immediate-early
period after surgery may further increase that risk. Conversely, a
delay of continuation of antiplatelet maintenance therapy will
significantly increase the risk of stent thrombosis, considering
that surgical procedure triggers platelet activation and
aggregation. Therefore, an early therapy with reversible
antiplatelet agent that could be titrated to a desirable level of
platelet inhibition and have ultra-short platelet function recovery
time could be beneficial in preventing stent thrombosis in that
category of patients. Moreover, this type of agent will be safe
because it may allow complete recovery of platelet function after
discontinuation in case of bleeding.
[0131] Cangrelor is a potent, reversible and specific P2Y.sub.12
receptor antagonist that would allow overcoming the limitations of
currently used dual antiplatelet therapy with aspirin and
clopidogrel thanks to its rapid onset and offset of action with
steady-state plasma concentrations that can be achieved within
minutes and titrated to modulate the level of platelet inhibition
and most importantly, it is rapidly metabolized with an short
half-life, allowing complete recovery of platelet function in less
than 60 min. Therefore, cangrelor could be an ideal antiplatelet
agent for managing platelet inhibition in early post-operative
period in patients with implanted stents requiring a surgical
procedure.
[0132] The optimal platelet inhibitory dose and regimen for
cangrelor infusion in post-operative period and transitioning to
oral antiplatelet therapy can be determined.
[0133] The patient population can be ACS patients with implanted
stents after PCI who require a major surgical procedure (CABG, GI
anastomoses, pulmonary resection, prostatectomy, orthopedic
procedures, etc.), N=40 subjects (4 groups with 10 subjects in each
group). Cangrelor infusion will be initiated 1-2 hours after
completion of surgical procedure at surgeons' discretion. The
subjects will be randomized into the following groups:
[0134] Group 1: Cangrelor 0.5 .mu.g/kg/min dose infusion for 24 hrs
transitioning to oral antiplatelet therapy with 300 mg of
clopidogrel loading dose after infusion discontinuation followed by
75 mg daily maintenance dose thereafter;
[0135] Group 2: Cangrelor 0.5 .mu.g/kg/min infusion for 24 hrs
transitioning to oral antiplatelet therapy with 600 mg of
clopidogrel loading dose after infusion discontinuation followed by
75 mg daily maintenance dose thereafter;
[0136] Group 3: Cangrelor 1 .mu.g/kg/min infusion for 24 hrs
transitioning to oral antiplatelet therapy after infusion
discontinuation transitioning to oral antiplatelet therapy with 300
mg of clopidogrel loading dose after infusion discontinuation
followed by 75 mg daily maintenance dose thereafter;
[0137] Group 4: Cangrelor 1 .mu.g/kg/min infusion for 24 hrs
transitioning to oral antiplatelet therapy after infusion
discontinuation transitioning to oral antiplatelet therapy with 600
mg of clopidogrel loading dose after infusion discontinuation
followed by 75 mg daily maintenance dose thereafter.
[0138] The primary endpoints will be: (1) acute sent thrombosis
during the 48 hrs after the surgical procedure, and (2) major and
minor bleedings during the 48 hrs after the surgical procedure.
[0139] The methods of evaluation will be: (1) platelet aggregation
using VerifyNow.RTM. P2Y12 test, (2) hemodynamic measurements, (3)
blood tests, (4) clinical observations for minor capillary bleeding
signs (petechiae, hematoma), (5) Diagnostic imaging of
intracranial, peritoneal and pleural cavities using CT, MRI, US,
when necessary to detect potential bleeding complications (blood
accumulation).
Example 5
Population Pharmacodynamic Evaluation of Cangrelor
[0140] Objective: The objective of this evaluation was to develop a
population pharmacodynamic model to describe the concentration
effect relationship between cangrelor exposure and the marker of
platelet aggregation, namely P2Y12 reaction units (PRU), as
measured by VerifyNow.RTM., Accumetrics in order to, among other
things, determine how best to transition from the bridge dose to
the PCI dose, and vice versa.
[0141] Data and Database Creation: The database created for this
evaluation included a total of 1102 PRU observations from 220
bridge and PCI patients. A summary of the demographics is provided
in Table 4. These patients were generally older and heavier than
volunteers.
TABLE-US-00004 TABLE 4 Summary of the Demographics of the Patients
Involved in the Study. Covariate (units) Mean Median SD Max Min Age
(yrs) 63 62 11 92 36 Weight (kg) 86.8 85.4 16 154 52 BMI (kg/m2)
29.5 29.1 5.07 50.1 19.4 Sex Male Female Number 161 59 CHAMPION
PCI/Platform Study (PCI) Platelet Substudy Bridge Number 104 116
Patient type PCI ACS Stent Number 54 69 97 PCI/substudy, 30
.mu.g/kg bolus + Cohort 1: Cohort 1: Treatment 4 .mu.g/kg/min 0.5
.mu.g/ 0.75 .mu.g/ Cohort 2: Group infusion kg/min kg/min 0.75
.mu.g/kg/min Number 104 5 6 105 ACS denotes acute coronary
syndrome. PCI denotes percutaneous coronary intervention.
[0142] Simulation Assessments: In order to address the
pharmacodynamic objectives and show how best to transition from one
dose to the other dose (i.e., Bridge and PCI), stochastic
simulation was performed in NONMEM. A PRU value of 208 was chosen
throughout the evaluation as the cutoff to evaluate the
effectiveness of varying doses of cangrelor in different patient
types. The results were evaluated graphically by generating 95%
confidence intervals and by summarizing the percentage of patients
expected to achieve a PRU value of 208 or less. For each simulation
scenario, 1000 patients were simulated using covariates drawn from
the original distribution of covariate values. Parameter precision
was not taken into account for these simulations.
[0143] Patients from the bridge subset of data were sampled. At
varying times after initiation of the bridge dose, the patient type
was switched to the PCI type (to reflect reduced sensitivity to
cangrelor) and the dose was increased to the PCI dose. The
percentage of subjects achieving the desired PRU result of 208 or
lower were tabulated. For completeness, the reverse transition
(from PCI to bridge) was also simulated, and results tabulated.
[0144] Description of PRU Pharmacodynamic Model: The PRU
pharmacodynamic model was a direct effect sigmoidal inhibitory
model with terms describing the between subject variability
included on the drug effect parameter (Emax) and baseline. An
additive residual error was used. The model incorporated a slowly
increasing baseline in bridge patients (attributable to the effect
of previous dosing with clopidogrel wearing off) and a slowly
decreasing baseline in PCI patients (owing to the thrombotic
stimulus of the stenting/PCI gradually lessening after the
procedure together with onset of effect of other post procedure
treatments). The model also included a covariate for patient type
on drug effect and the effects of age and sex on baseline. The
equations for the final PRU pharmacodynamic model are provided
below.
BaselinePRU = .theta. 6 * ( 1 - sex * .theta. 11 ) * ( Age 30 )
.theta. on * exp ( .eta. 5 ) ##EQU00001## Eff = .theta. 7 * ( 1 -
patient type * .theta. 10 ) * exp ( .eta. 4 ) ##EQU00001.2## IC 50
= .theta. 8 ##EQU00001.3## .gamma. = .theta. 9 ##EQU00001.4## if (
Study - 1 ) wearoff - .theta. 13 else .theta. 14 ##EQU00001.5##
DrugEffect = Eff * Cp T IC 50 T + Cp T ##EQU00001.6## PRU =
BaselinePRU - DrugEffect - wearoff * Time ( hrs )
##EQU00001.7##
[0145] The parameters were estimated with good precision with the
exception of the age effect on baseline. All other diagnostics and
model evaluations suggested that the model performance was
acceptable. The parameters from the model are provided in Table
5.
TABLE-US-00005 TABLE 5 Parameter estimates for base PRU
pharmacodynamic model. Between Parameter Population SE Subject SE
(Units) Mean (CV %) Variability (CV %) Baseline 215 7 23.22 15 Wear
off PCI (1/h) -3.15 13.7 Wear off bridge (1/h) 0.838 7.3 Age effect
0.228 39.7 Gender effect -0.162 25.3 Drug Effect 148 6.2 19.21 31.7
PCI patient effect -0.624 17 IC50 0.0717 35.4 NE NE Gamma 1.71 21
NE NE Additive Residual Error 62.6 2.7 NE--not estimated.
[0146] Several covariates were identified in this evaluation. There
was an effect of gender on the baseline PRU, with females having a
16% higher baseline PRU than males. Age was also found to be
important on the baseline PRU value. The impact of age is provided
in Table 6.
TABLE-US-00006 TABLE 6 Effect of age on baseline PRU. Age (yrs)
Baseline PRU Percent of Reference 30 215 100 40 230 107 50 242 112
60 252 117 70 261 121 80 269 125
[0147] Over the age range from 30 to 80 years, the baseline PRU
would be expected to increase by 25%. There was a larger impact of
patient type (i.e., PCI patient versus bridge patient) on the drug
effect which is shown in FIG. 5. This impact is a 62% decreased
effect in PCI relative to bridge and shows why the percentage of
simulated PCI patients achieving the threshold response of 208 is
somewhat lower than seen in the bridge patients.
[0148] Simulation Results--Evaluation of the Probability of
Achieving the Desired PRU Cutoff: The probability of the PCI and
bridge patients achieving the desired PRU cutoff value of 208 is
provided for the overall indication in Table 7.
TABLE-US-00007 TABLE 7 Probability of achieving desired PRU result
by patient type - overall findings. Study Patient Type Dose
Probability 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min 0.827462 2
Bridge 0.75 .mu.g/kg/min 0.961949
[0149] As can be seen, despite the lower dose used for the bridge
patients, the probability of achieving the threshold is higher in
these patients than the PCI patients because the PCI patients had a
higher immediate thrombotic stimulus.
[0150] Similarly the probability of maintaining the PRU below the
threshold after stratification of patients by weight over the range
of weights in the database showed no overall trends (Table 8),
suggesting that the drug concentration is sufficient to provide
approximately 80% at or below threshold for PCI patients and over
90% at or below threshold PRU for bridge patients with the
suggested dose.
TABLE-US-00008 TABLE 8 Probability of achieving desired PRU result
by patient type and weight. Weight Patient Range Probabil- Study
Type Dose (kg) ity 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (50,
80) 0.839885 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (80, 90)
0.795222 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (90, 100)
0.7975 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (100, 120)
0.87275 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (120, 160)
0.856 2 Bridge 0.75 .mu.g/kg/min (50, 80) 0.95797 2 Bridge 0.75
.mu.g/kg/min (80, 90) 0.98004 2 Bridge 0.75 .mu.g/kg/min (90, 100)
0.952081 2 Bridge 0.75 .mu.g/kg/min (100, 120) 0.957313 2 Bridge
0.75 .mu.g/kg/min (120, 160) 0.9915
[0151] There was no marked trend in the probability of patients
achieving the threshold with age (Table 9).
TABLE-US-00009 TABLE 9 Probability of achieving desired PRU result
by patient type and age. Age Patient Range Probabil- Study Type
Dose (yrs) ity 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (30, 50)
0.896722 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (50, 60)
0.806719 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (60, 70)
0.836735 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (70, 80)
0.778786 1 PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min (80, 100)
0.791333 2 Bridge 0.75 .mu.g/kg/min (30, 50) 0.994444 2 Bridge 0.75
.mu.g/kg/min (50, 60) 0.98919 2 Bridge 0.75 .mu.g/kg/min (60, 70)
0.984217 2 Bridge 0.75 .mu.g/kg/min (70, 80) 0.93135 2 Bridge 0.75
.mu.g/kg/min (80, 100) 0.869444
[0152] There was no marked trend in the probability of patients
achieving the threshold with gender (Table 10).
TABLE-US-00010 TABLE 10 Probability of achieving desired PRU result
by patient type and sex. Patient Study Type Dose Sex probability 1
PCI 30 .mu.g/kg bolus with 4 .mu.g/kg/min Male 0.866044 1 PCI 30
.mu.g/kg bolus with 4 .mu.g/kg/min Female 0.754583 2 Bridge 0.75
.mu.g/kg/min Male 0.982444 2 Bridge 0.75 .mu.g/kg/min Female
0.901222
[0153] These results support the selection of a higher dose for PCI
patients than for Bridge patients and suggest that there should be
no need to adjust dose for age or gender.
[0154] Transition from Bridge to PCI: The results of the simulated
transition from the bridge setting (0.75 .mu.g/kg/min) to the PCI
setting (4 .mu.g/kg/min) with and without the administration of an
IV bolus loading dose for PCI (30 .mu.g/kg) are provided for a
reference male patient in FIG. 6 and FIG. 7, respectively. As was
seen with the evaluation of probability of achieving the threshold
PRU response, the probability is generally lower for the PCI than
bridge patient in all settings. The same scenarios were simulated
in a reference female patient with and without the IV bolus dose
(FIG. 8 and FIG. 9, respectively). The benefit of adding a bolus
dose when transitioning from bridge to PCI is somewhat limited, but
the probability of maintaining the PRU value below 208 is higher
with the recommended loading dose than without such IV bolus dose
prior to PCI.
[0155] Transition from PCI to Bridge: The results of the stochastic
simulations from the PCI setting (30 .mu.g/kg bolus with 4
.mu.g/kg/min) to the bridge setting (0.75 .mu.g/kg/min) are
provided for the same virtual male and female patient in FIG. 10
and FIG. 11, respectively. In these simulations, patients received
the recommended PCI dose for 2 hours, then were transitioned
directly to the recommended bridge dose for 8 hours. PRU samples
were taken hourly. Because these virtual patients were simulated to
reflect a PCI patient (and who would not therefore have had a high
dose of cangrelor prior to PCI), the wearing off effect seen with
the bridge study was turned off. However the ability of a subject
to respond to cangrelor was changed once bridge dosing was
initiated.
[0156] Although these figures suggest a substantial difference
between males and females, the determined probability of achieving
a PRU below the threshold of 208 was similar. Thus these figures
reflect the inherent variability of the PRU assay more than any
difference in inherent responsiveness to treatment.
[0157] The results of the stochastic simulations suggest that when
transitioning from the bridge setting to the PCI setting, or vice
versa, there is no need to modify the cangrelor dosing (e.g., dose
titration) from that which is routinely used for these indications.
PCI patients being transitioned to surgery can be switched from 4
.mu.g/kg/min cangrelor directly to 0.75 .mu.g/kg/min cangrelor.
Surgical patients being transitioned to PCI can be switched
directly from 0.75 .mu.g/kg/min cangrelor to 4 .mu.g/kg/min
cangrelor, either with or without the 30 .mu.g/kg bolus cangrelor
dose.
[0158] Those of ordinary skill in the art will recognize that many
modifications and variations of the present invention may be
implemented without departing from the spirit or scope of the
invention. Thus, it is intended that the present invention cover
the modification and variations of this invention provided they
come within the scope of the appended claims and their
equivalents.
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